We identify and topographically localize ocular inflammatory, degenerated, and tumor cells, and their products, in patient specimens and animal samples and analyze them by routine pathology, immunohistochemistry, and molecular pathology. The application of cutting-edge technology, such as microdissection combined with molecular techniques including PCR, RT-PCR, RQ-PCR and RFLP, allows us to provide more accurate pathological diagnosis (assessment) and pathogenesis of the disease, and guides us in selecting an appropriate therapy for the patient. We learn a great deal about the mechanisms of different ocular diseases from various animal models with ocular disorders. Using animal models, we can also access the efficacies of different therapeutic agents for various ocular diseases. This helps us better understand disease mechanisms and select superior therapies that target specific diseases in our human patient population. In FY2009, we accomplished the following in our research: 1. Molecular Pathology of Age-Related Macular Degeneration (AMD): AMD is a debilitating disease of the retina, which manifests clinically with the loss of central vision and pathologically with the accumulation of drusen, RPE degeneration, photoreceptor atrophy, and some with choroidal neovascularization (CNV). While several risk factors, including age, race, smoking, and diet have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear. Treatment options for the condition are similarly limited. The molecular pathological findings in both humans and animal models of AMD include genetic variations in CFH, CX3CR1, and ARMS2/HtrA1 and other molecules and cells implicated in inflammation (e.g., macrophages and microglia), apoptosis, cholesterol trafficking, angiogenesis (e.g., VEGF expression), and oxidative stress (e.g., the role of mitochondria). We also confirmed a significant association between the HtrA1 promotor polymorphism, smoking, and age-related macular degeneration in four case-control samples. Furthermore, we demonstrated enhanced expression of HtrA1 in the macular lesions from AMD archived slides. We detected C. pneumoniae DNA from the peripheral blood of 148 advanced AMD patients and 162 controls and from microdissected macular cells from 59 AMD and 16 age-matched, non-AMD archived slides. We found a possible association between AMD and C. pneumoniae infection, although the CFH genotype may not be directly involved in the pathogenesis of C. pneumoniae infection-mediated AMD. 2. Ocular Lymphoma: We have proposed new nomenclature: Retinal Lymphoma for primary intraocular lymphoma, as it originates in the retina. We review this high-grade malignancy, usually of B-cell type, and its association with a poor prognosis because of frequent central nervous system (CNS) involvement. Recent evidence suggests that the putative cell of origin is either a late-germinal center or an early post-germinal center B-cell. We have confirmed elevations of interleukin-10 in ocular fluids in patients with B-cell retinal lymphoma and the IgH gene rearrangements of ocular B-cell lymphoma cells. Ocular images (fluorescein angiogram and OCT) are helpful adjuncts for diagnosis of retinal lymphoma. The vast majority of primary intraocular lymphomas are malignant B-cells, while intraocular T-cell lymphomas are rare. We reported a case of metastatic nasal natural killer T-cell (NKT-cell) lymphoma to the retina. 3. New Pathology and Pathogenesis of Ocular Diseases: We reported several novel pathologic findings including: limbal stem cell deficiency arising from systemic chemotherapy with hydroxycarbamide, Pseudomonas aeruginosa DNA in a chorioretinal lesion associated with chronic granulomatous disease, an inflammatory component in choroideremia, recalcitrant granulomatous sclerouveitis in a Wegeners patient who failed anti-TNF&#945;therapy, and an autoimmune retinopathy in systemic lupus erythematosus. These new pathological and molecular pathological findings provide insight to various ocular complications of the aforementioned systemic diseases. 4. Experimental Models for Various Ocular Diseases: We reported that a diet enriched in EPA and DHA can ameliorate the progression of retinal lesions in Ccl2/Cx3cr1 deficient mice, our mouse model of AMD. The findings in these mice are in line with the epidemiological studies of AMD risk reduction by long chain n-3 fatty acids. These results further provide the scientific basis for the use of omega-3 fatty acids and their biologically active derivatives in the prevention and treatment of AMD. In collaboration with Drs. Caspi, Gery, Hooks, and Nussenblatt of the NEI, and Dr. Restifo of the NCI, several new models and mechanisms of ocular inflammation and immunotherapy in melanoma have been discovered and published. These are further described in their annual reports.